All About Wilms' Tumor

Wilms' tumor (WT) is also known as nephroblastoma, a medical word that basically means an embryonic ("blast") tumor ("oma") of the kidney ("nephro"). It is named after Max Wilms, the physician who first described this disease. Wilms' tumor represents about 6% of all childhood cancers. Overall, it is the fourth most common tumor of childhood, and is the most common pediatric tumor of the abdomen. The tumor usually only affects one kidney (unilateral WT), but can involve both kidneys (bilateral WT) in up to 4-8% of cases. In about 7% of cases, there is more than one tumor in the same kidney (called multicentric).

How common is Wilms' Tumor?

There are just under 500 new cases of WT yearly in the United States.

Who gets Wilms' Tumor?

WT is a cancer of children, a pediatric cancer. Both boys and girls can be affected, with girls having a slightly higher risk. Wilms’s tumor is also more common in African Americans. The median age at time of diagnosis is 42 months in boys and 47 months in girls. More than 90% of all WT are diagnosed before the age of 5 years.

What causes Wilms' Tumor?

In normal human development, each person has an entire set of paired chromosomes; one half of the pair is from the mother and the other half is from the father. Each chromosome is further divided into smaller sections called genes, which contain a person's unique DNA, or "genetic code". This code is used to build very important proteins in the body. Wilms is thought to result from accidental loss of certain parts of DNA, known as tumor suppressor genes. These genes are responsible for regulating cell growth. When these suppressor genes are lost, there is an overgrowth of kidney cells, which results in a cancer (tumor) forming in the kidney. There have been several tumor suppressor genes that have been linked with wilms tumor, including WT1, WT2, and P53, among others.

The accidental loss of this DNA or gene that leads to WT happens early during development, typically before birth. A majority of the cases are "sporadic", meaning that WT does not "run in the family”. It is not clear exactly what triggers these genes to be deleted and there are no known causes of WT (like anything that a child or mother could have been exposed to). Because each person has 2 copies of each gene, both copies of a tumor suppressor gene have to be missing to develop WT. If only one copy of the gene is missing, a person is a carrier of the mutation, but does not necessarily have the disease.

Only about 1% of WTs are “familial” or run in the family. In these patients, either the mother or the father carries a gene deletion, and then passes this on to the child. The child is thus born with only one copy of the gene, and if that is somehow deleted, he or she will develop WT.

About 10% of WT cases are associated with other medical problems and together these medical problems are called syndrome. Examples are the WAGR syndrome, which includes Wilms Tumor, Aniridia, (eyes without the irises, or colored parts), Genitourinary malformations (such as genital or kidney deformities), mental Retardation, and the Beckwith-Wiedemann syndrome, which is marked by abnormally large body size and overgrown abdominal organs. There is about a 30% chance of developing WT in people with WAGR syndrome, and a 6% chance of developing WT in people with Beckwith-Wiedemann syndrome. Another syndrome that has been associated with WT is Denys-Drash syndrome. People with Denys-Drash syndrome have kidney disease, ambiguous genitalia, and WT.

Are all Wilms' Tumors the same?

No. The two main types of WT are favorable histology (FH), which makes up more than 80% of cases, and the less common, unfavorable or anaplastic histology (UH). As one might expect from the names, the favorable WTs have a better prognosis than the unfavorable type. The amount of anaplastic histology (cell changes seen with a microscope) that is present in the tumor is also important in determining treatment in WT. The classification is based on unique microscopic appearances that have been associated with the aggressiveness of the tumor.

Other factors may also contribute to prognosis and treatment choices. Anaplasia is a more aggressive type and is present in about 6% of cases. In addition, younger children (less than two years old) tend to have a better prognosis. Recent research has suggested that there are certain genetic mutations that predict a worse prognosis. One mutation, associated with poorer prognosis, causes a loss of heterozygosity (LOH) at 16q and 1p. This means that a portion of a chromosome has been lost.

Finally, WT may be metastatic or have spread to other areas of the body, including the lung and the liver, which will be evaluated for if WT is diagnosed.

What symptoms does a Wilms' Tumor cause?

The overwhelming majority of kids present with an abdominal mass, which may or may not be associated with abdominal pain from pressure, bleeding, or bowel rupture secondary to the growing mass. Other possible symptoms include fever (23%) and hematuria, or blood in the urine (21%). Less likely are things like high blood pressure, hernias, or heart failure. If WT is diagnosed at an advanced stage, it can present with disease that has spread (metastasized) to the lungs, which in some cases could cause respiratory symptoms. Additionally, any child with WT should be evaluated for abnormalities of the genitalia or urinary tract. They should also be carefully examined for any of the traits related to the genetic syndromes mention above, as WT may be part of a broader syndrome. Routine screening in people with genetic defects known to be associated with WT may be of benefit, however this is controversial.

How is Wilms' Tumor evaluated?

Once a WT is suspected, the medical workup starts with a thorough history, including family history and a physical examination. Radiologic testing typically includes the following studies:

Abdominal ultrasound is usually the first test ordered to evaluate the kidneys. Doppler ultrasound can also be used to evaluate blood flow to the kidneys and whether the tumor has spread into the blood vessels of the kidney. Abdominal CT scan is also recommended to determine if there has been any spread to other organs, as well and if there is any disease in the other kidney. CXR or CT scan of the chest is used to determine if the disease has spread to the lungs.

How are Wilms' Tumors staged?

There are currently two widely used staging systems for WT, the National Wilms' Tumor Study (NWTS) and the International Society of Pediatric Oncology (SIOP). The NWTS system is used in United States and will be discussed here.

Stage I (~40% of patients)

Stage I WT is defined as tumor limited to the kidney and completely removed by surgery. The tumor is not ruptured at any time during the surgery. The blood vessels around the kidney are not involved with tumor. There is no remaining cancer visible beyond the area where the surgeon operates.

Stage II (~20% of patients)

Stage II WT is when tumor extends beyond the kidney but is completely removed by surgery. The extension beyond the kidney can be due to blood vessel involvement, local tumor "spillage" during surgical removal, or other nearby tumor extension. If there was a biopsy of the tumor, it is considered stage II. There is no remaining cancer visible at or beyond the area where the surgeon operated.

Stage III (~25% of patients)

Stage III WT is when all of the visible tumor can not be completely removed with surgery, and there is tumor left behind but only in the abdomen.

Stage IV (~10% of patients)

Stage IV WT is defined as disease that has spread outside of the abdomen via the blood, also called hematogenous metastases. The areas in the body where WT can spread include the lung, liver, bone, brain, or to a combination of these sites.

Stage V (5% of patients)

Stage V WT is the presence of tumor in both kidneys at initial diagnosis.

Risk Group

Instead of stage, your doctor may discuss your risk group, which helps to guide treatment (very low, low, standard, higher, or bilateral). These risk groups are based on the stage of the tumor, the age of the patient, the weight of the tumor, the histology of the tumor and some of the genetics of the tumor (Loss of Heterozygosity or LOH). See the chart at the end of this article for more detailed information on the classification of risk groups.

How are Wilms' Tumors treated?

In general, pediatric cancers are rare compared to adult cancers and compared to other, non-cancer pediatric diseases. Given this fact, all children with WT should be considered for entry into a clinical trial. Treatment should involve a multidisciplinary team of cancer specialists, including a pediatric surgeon or urologist, a pediatric radiation oncologist, and a pediatric oncologist, all of whom have some experience in treating WT patients.

Extensive research in the treatment of WT has been done by the National Wilms' Tumor Study Group, (WTSG) which was established in 1969 and is now part of the Children's Oncology Group (COG). Additionally, there have been several studies in Europe conducted by the International Society of Pediatric Oncology. The difference between the American and the European strategies for treating WT is that in American, upfront surgery is preferred whereas the Europeans favor chemotherapy prior to surgery. The findings of the four National Wilms' Tumor Studies (NWTS) conducted by the WTSG have helped establish the current treatment guidelines in the United States. These guidelines typically incorporate a combination of surgery, chemotherapy and, in some patients, radiation therapy. The development of these treatment protocols demonstrates the power of clinical trials and the collaboration of researchers around the world. At one time, a diagnosis of WT was almost always fatal. Currently over 85% of patients with local disease are cured and those with metastatic disease have over 70% chance of survival.

General Treatment Modalities

Surgery

The most important role of surgery is to entirely remove the tumor without rupturing it, and visually assessing the surrounding area for possible local disease spread. Total removal of the involved kidney, known as a radical nephrectomy, together with sampling, or "biopsy" of specific abdominal lymph nodes, is the surgical procedure of choice.

Chemotherapy

Patients with very large or extensive tumors that cannot be feasibly and safely removed by surgery can be considered for preoperative chemotherapy. Prior to starting chemotherapy, a biopsy through the abdominal skin (percutaneously) should be performed to officially establish the diagnosis. Preoperative chemotherapy makes tumor removal easier and may reduce the frequency of surgical complications.

The chemotherapy drugs commonly used in WT patients are dactinomycin, vincristine, doxorubicin. etoposide and cyclophosphamide. Not all medicines may be used for everyone. For example in some early stage WT only vincristine and actinomycin may be used after surgery. Mesna may be used, which is not a chemotherapy drug, but is a medication used to protect the bladder wall from the harmful effects of the chemotherapy cyclophosphamide.

Radiation Therapy

There is a very limited role of radiation therapy in the treatment of WT (about 25 to 30% of patients will require radiation), and is restricted largely to treating symptoms caused by widespread, Stage IV disease. The use of radiation as part of the definitive treatment of non-Stage IV patients is discussed below in the stage-specific subsections. Of note, radiation should generally begin within 9 days of the surgery to minimize the risk of disease spread. Radiation may be delivered either to the flank where the tumor was or it may be used to treat the entire abdomen. Reasons to treat the entire abdomen include rupture of the tumor either before or during surgery, if the tumor was very large or if there was diffuse involvement of the abdominal cavity with metastatic disease.

Special Notes

The chemotherapy drugs dactinomycin or doxorubicin should not be administered during radiation therapy, as this can worsen the side effects of the radiation (also called “radiation recall”).

Risk group-specific Treatment Guidelines

Very low and low risk Favorable Histology Wilms' Tumor

Nephrectomy (removal of the kidney) with lymph node sampling and chemotherapy with vincristine and dactinomycin.

Standard risk Favorable Histology Wilms' Tumor

Nephrectomy (removal of the kidney) with lymph node sampling, abdominal irradiation, and chemotherapy with vincristine, doxorubicin, and dactinomycin.

Higher risk favorable histology Wilms' Tumor

Nephrectomy (removal of the kidney) with lymph node sampling, abdominal and lung irradiation, and chemotherapy with vincristine, doxorubicin, and dactinomycin.

Unfavorable Histology Wilms Tumor

Is treated with nephrectomy and different chemotherapy medication schedules, which may include: Cyclophosphamide, carboplatin, and etoposide, vincristine, doxorubicin, and irinotecan.

Bilateral Wilms' Tumor

In general, biopsy does not need to be performed if the diagnosis is certain based on imaging. Chemotherapy is given based on the histology and stage first.

Next, the patient is reassessed with imaging and a surgery is planned between week 6 and 12 of treatment with plan for additional chemotherapy after that.

Prognosis

In stage I & II disease, an average of approximately 90% of patients (both FH and UH) will be cured. About 85% of all patients with stage III disease will be cured and 66% of all patients with stage IV tumors and those with unfavorable histology will be cured. Patients who have a recurrence of their tumor after treatment can be treated with further therapy, which can result in cure.

Many parents want to know the prognosis for their child, but it is important to remember that these numbers are estimates based on large groups of kids, and are difficult to apply to any one case. Many factors, including stage, histology and response to treatment, play a role in the outcome of treatment and the reported prognoses are only a rough estimate.

Follow Up and Long-term Effects

After treatment is finished, your child will have a plan for follow up care, based on the initial stage and histology of the tumor. At first, the visits with their physician will be frequent, but as time passes, there will be more and more time in between visits. These visits may include blood tests and radiology scans. It is important to continue to be seen by a primary care provider who has information about the cancer treatment, and can follow your child for any long term concerns in conjunction with the oncology team.

There are several side effects associated with both radiation and chemotherapy that can occur months to years after treatment, often called “late effects”. These include the risks of damage to the heart, liver, lungs, and kidneys, as well as decreased height due to decreased growth of the bones of the spine. Research has found that childhood cancer survivors are at higher risk for chronic health conditions than those who have not had cancer. It is important for survivors to incorporate healthy lifestyle behaviors, such as exercise, healthy diet, not smoking and regular medical and dental care, to reduce their risk of these chronic health concerns.

Having one functioning kidney can raise concerns for damage to or a decrease in the functioning of the kidney and high blood pressure, as the kidney regulates blood pressure. The remaining kidney can also be damaged with treatment. Children treated for WT may be at increased risk for developing second cancers. This risk depends on the intensity of their therapy and certain genetic factors. These patients should be followed life-long by a survivorship clinic in cooperation with a primary care provider.